We generated mice with Gs-alpha deficiency in skeletal muscle (MGsKO mice) by repeated matings of muscle heavy chain promoter -cre recombinase transgenic mice with floxed Gs-alpha mice which have loxP recombination sites surrounding Gs-alpha exon 1. Results to date show that MGsKO mice have normal survival and no obvious physical phenotype. MGsKO mice had normal growth and body weight with composition and no changes in food intake and energy expenditure. These results show that loss of Gs-alpha in muscle does not appear to affect whole body energy metabolism on a regular calorie diet. Studies on high fat diet also show no evidence of differences in metabolism. Studies in glucose metabolism (baseline serum chemistries, glucose and insulin tolerance tests, hyperinsulinemic euglycemic clamp studies, and glucose uptake in isolated muscles) show that MGsKO mice are glucose intolerant despite the fact that the mice have normal insulin secretion and hypoglycemic response to administered insulin. In fact studies in isolated muscles show basal glucose uptake to be increased and with no change in glucose uptake in the presence of maximal insulin stimulation, although the increase from baseline with insulin was lower in muscles from MGsKO mice. In addition, muscle glucose uptake in response to the AMP analog AICAR was unaffected, indicating that AMP kinase and its downstream pathways remain intact. Studies are ongoing to try to understand the mechanisms underlying the glucose intolerance in MGsKO mice, in particular focusing on whether Gs-alpha stimulates other insulin-independent pathways which lead to glucose uptake. Skeletal muscles in MGsKO show significant atrophy with reduced fiber cross-sectional area. In addition, there is a switch in from type 1 (white, fast-twitch) to type 2 (red, slow-twitch) fibers based upon myosin heavy chain subtypes and kinetic properties even though the muscles have reduced mitochondrial content and oxidative capacity and reduced expression of PGC-1alpha, a known transcriptional inducer of mitochondrial oxifation and switch to type 1 fibers. Therefore in MGsKO mice there is a dissociation between the fiber type switch and the expected changes in metabolic properties.